Proc Natl Acad Sci U S A 1993 Jun 15;90(12):5384-90

Gaucher disease as a paradigm of current issues regarding single gene mutation
of humans.

Beutler E

Department of Molecular and Experimental Medicine, Scripps Research Institute,
La Jolla, CA 92037.

Abstract
Gaucher disease is a glycolytic storage disease caused by a deficiency in
activity of the catabolic enzyme glucocerebrosidase. Over 35 different mutations
have been documented, including missense and nonsense point mutations, splicing
mutations, deletions and insertions, a fusion gene, and examples of gene
conversion. Gaucher disease is most common in the Ashkenazi Jewish population,
in which just five of the mutations in this population account for 98% of the
disease-producing alleles. Each of these mutations is found in the context of a
single haplotype, a finding consistent with a single origin of each mutation.
Although it is clear that these mutations provide a selective advantage in the
Jewish population and thus constitute a balanced polymorphism, the nature of the
advantage is unknown. Gaucher disease can be treated symptomatically, by
administration of the missing enzyme, by allogeneic bone marrow transplantation,
and potentially by gene transfer into hematopoietic stem cells. Increasing
understanding of this disease has, as in other genetic disorders, created a host
of social and ethical dilemmas regarding matters such as the cost of treatment
for rare diseases and the advantages and disadvantages of population-targeted
genetic screening.